Journal articles on the topic 'Fondazione Origine'

Nell’antica Grecia, il mito delle Amazzoni, che, nell’immaginario collettivo greco, rappresentavano l’elemento “altro”, è spesso associato a tradizioni di fondazione e di eponimia in rapporto a città, soprattutto nella Ionia e nell’Eolide d’Asia Minore. Queste tradizioni si possono rintracciare in racconti locali, che si sono conservati fino all’età imperiale romana, in un momento in cui, in particolare, si assiste ad una ripresa delle tradizioni greche arcaiche e classiche durante la seconda sofistica. L’epoca dell’imperatore Adriano, più di ogni altra, sarebbe stata importante per la rinascita ed il recupero di questi miti di fondazione, in quanto molte città ioniche ed eoliche (come Efeso, Smirne, Cuma e Mirina) creavano un nesso con il loro passato e con la loro origine per mezzo della figura dell’Amazzone, rappresentata anche sulla monetazione locale, con l’obiettivo di affermare la loro antichità e priorità: tali tradizioni sono attestate anche nelle fonti letterarie. Grazie alla remota antichità ed adattabilità, il mito di fondazione basato sulle Amazzoni attraversò diversi processi di rielaborazione e rifunzionalizzazione e fu riutilizzato come “paradigma” in Asia Minore, soprattutto in età imperiale, per sottolineare l’archaiologia delle antiche poleis. Queste elaborazioni, fondate su antiche tradizioni mitiche locali, sono state determinanti per riaffermare e rivendicare l’identità culturale ed etnica dei Greci sotto l’Impero romano in un preciso momento storico. Obiettivo del presente lavoro è indagare i processi di costruzione e ri-costruzione dell’identità cittadina attraverso l’analisi delle fonti relative ai racconti di fondazione e di eponimia attestati in Ionia e in Eolide in relazione al particolare contesto legato al revival delle tradizioni locali greche in età imperiale.

C'è poca documentazione sull'origine della psicoterapia della Gestalt in Canada e sulla nascita della ricerca in questo approccio. Questo articolo fornisce informazioni sulla fondazione dell'Istituto di Gestalt di Toronto (GIT), che ha preso origine dalla comunità gestaltica del Lago Cowichan. Si riportano estratti di una intervista al prof. Leslie Greenberg, un membro della prima classe di specializzati al GIT, considerato il padre della ricerca dagli psicoterapeuti della Gestalt. Questi brani dell'intervista fanno luce sulla nascita della ricerca gestaltica, attraverso un viaggio nelle prime esperienze di formazione di Greenberg, e nelle sue prime ricerche in ambito gestaltico, fino alla risoluzione, nel corso degli anni, del suo rapporto con la psicoterapia della Gestalt.

In occasione della personale di Giuseppe Capogrossi alla Galleria L'Attico di Roma dal 10 al 30 marzo 1962, venne pubblicato un catalogo ideato dal poeta e critico d’arte Emilio Villa, con due suoi testi. Il primo, steso in occasione della mostra, presenta una seconda parte ideata e scritta in latino nei primi anni Cinquanta come lettura fonetica delle strutture segniche di Capogrossi, e il secondo, in francese, datato settembre 1953, è anch'esso pensato come lettura fonetica.Il saggio analizza come Villa ricrei verbalmente e visivamente le articolazioni segniche di Capogrossi, attingendo ad ambiti semantici differenti, e mette in luce le fonti visive di carattere arcaico e primitivista che Villa individua nella sua lettura del lavoro dell’artista e che suscitavano l’interesse di artisti e critici a Roma tra la fine degli anni ’40 e i primi anni ’50, vicini all’ambiente della Fondazione Origine e della rivista “Arti Visive”.

Il concetto di "evento" è usato in alcuni campi di ricerca della sociologia dell'ambiente e del territorio, ma non ha trovato sinora una definizione univoca e sviluppi coerenti. Tuttavia, esso è al centro di numerosi dibattiti nella filosofia contemporanea, così pure come in altri saperi. Il presente articolo esamina alcuni aspetti di tale riflessione, cercando di trarre da essa indicazioni per una più solida fondazione dell'idea dell'evento spaziale, inteso come fenomeno imprevisto e contingente, che si riferisce non unicamente agli effetti delle interazioni sociali, ma coinvolge al tempo stesso una molteplicità di elementi non-umani dotati di specifica agency, siano essi entità naturali o tecnologiche. Questo compito richiede anche di definire il rapporto tra l'evento e la situazione da cui prende origine, come pure le modalità con cui esso può dar vita ad una trasformazione radicale di questa. Basandosi su tali considerazioni, l'articolo si conclude ponendo la questione della sindemia di Covid-19 come evento catastrofico, dotato tuttavia di una potenzialità di trasformazione della situazione a vari livelli spaziali.

Com o presente artigo pretende-se apresentar a fundação laica da moral de Arthur Schopenhauer, mostrando como o discurso moral schopenhaueriano se articula e descrevendo as duas condições indicadas pelo filósofo para o alcance da negação da vontade de vida: a ascética-contemplativa do gênio, reservada a poucos eleitos, e a compaixão, aberta à maior parte dos homens. A pré-disposição à compaixão é individual e inata, assim como o caráter do qual ela se origina. Todavia, o compadecer-se, algo entendido como uma inclinação natural que permanece in potentia, pode ser suscitado também pela experiência da própria dor, mediante uma “segunda e melhor navegação”, o schopenhaueriano deuteros plous.

STORIA E RAZIONALISMO NELLA CITTA ANTICAViene trattato l'intreccio tra storia e razionalismo nell'organizzazione dello Stato nel mondo antico. Si dimostra che la vita politica greca si basava sul razionalismo e che la Storia veniva usata, ma subordinandola a speculazioni razionali. Ciò è provato dall'importanza degli Atti di fondazione mitici e dalla manipolazione della documentazione storica per fini politici. Vengono trovate le origini del razionalismo politico greco nelle origini della polis nel primo periodo arcaico. L'articolo termina con una discussione sul rapporto tra il razionalismo politico greco e lo sviluppo della polis in Etruria e Roma arcaica.

Renzo Canestrari ha promosso presso l'Università di Bologna gli studi di storia della psicologia al fine di comprendere sia le molteplici radici della psicologia scientifica, sia il tormentato processo di sviluppo della psicologia italiana, nel suo periodo di fondazione e in quello della rifondazione negli anni '50 e '60. Egli affidò all'allievo Giuseppe Mucciarelli, che proveniva da studi filosofici ed epistemologici, il compito di approfondire la conoscenza delle basi storiche ed epistemologiche delle scienze psicologiche. Negli anni '80 e '90 l'attività di Mucciarelli fu febbrile e incessante, facendo di Bologna uno dei più autorevoli centri di ricerca italiani nel campo della storia della psicologia. Mucciarelli ha condotto un gran numero di studi su come gli orientamenti positivisti, psicofisici e fenomenologici europei abbiano influenzato il primo sviluppo della psicologia in Italia.Nello stesso periodo Nicoletta Caramelli, analizzando i rapporti tra la storia della psicologia e quella delle scienze umane, ha gettato nuova luce sulle origini del cognitivismo e sulla transizione in Italia dalla psicologia della Gestalt alla psicologia cognitiva.

A retrospective analysis was performed with the aim of understanding whether the risk factors showed in the literature for medication-related osteonecrosis of the jaws (MRONJ) in cancer patients are also relevant in osteoporotic patients taking antiresorptive drugs (ARDs). Data were retrospectively pooled from health records of patients on ARDs who requested a dental visit between January 2006 and April 2020 in the Dental Unit at Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, University of Milan. A total of 434 patients were included. The following variables were collected: sex, age, smoking habit, type of ARD, duration of treatment, route of administration, therapeutic indication, concurrent systemic therapies and pathologies. Statistical analysis confirmed the relevance of chemotherapy, smoking, and immunosuppressive drugs as risk factors. In addition, a higher frequency of MRONJ in osteoporotic patients was reported in our cohort in association with an immunodeficiency disorder of variable origin. In conclusion, the identification of individual risk-profile before dental treatments is crucial for prevention. Anamnesis should include main risk factors, such as immunosuppression, dental extractions, smoking, trauma, and poor dental health. Nevertheless, our suggestion for dental professionals is to conduct a complete medical history of patients who mention long-term per oral therapies with ARDs for osteoporosis. Osteoporotic, as well as cancer patients, may also benefit from periodic monitoring of the ARDs therapy in order to prevent MRONJ.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease of controversial origin recently recognized as a neoplasm deriving from plasmacytoid dendritic cells (pDCs). Nevertheless, it remains an orphan tumor with obscure biology and dismal prognosis. In this study, we aimed to: 1) molecularly define the cellular counterpart of BPDCN and its relationship with other leukemias; 2) identify genes and cellular programs deregulated in the tumor; and 3) delineate novel potential therapeutic targets. To address these issues we collected and studied by gene expression profile (GEP) 27 BPDCN cases as well as 8 samples of non neoplastic pDCs. Further, a panel of samples including, myeloid precursors (MPs, N=4), lymphoid precursors (LPs, N=9), acute myeloid leukemias (AMLs, N=132), and acute lymphoblastic leukemias (ALLs, N=155) was analyzed. Validation was performed by immunohistochemistry (IHC) on tissue-microarrays, while functional experiments were carried out by using the CAL-1 cell line (derived from a BPDCN case). First, we recognized the cellular derivation of BPDCN, which proved to originate from the myeloid lineage and in particular from resting pDCs. Second, by comparing the GEP of BPDCN and resting pDCs, we identified genes and cellular programs deregulated in the tumor. Following, based on an integrated bio-informatic approach, including four different tools, we uncovered the aberrant activation of the NF-kB pathway that was confirmed in independent assays. Interestingly, among other molecules, we identified BCL2 and IRF4, two well known NFkB targets, as aberrantly upregulated in neoplastic samples and confirmed this observation by IHC. We then tested whether NFkB inhibition could represent a potential therapeutic strategy in this setting. We treated BPDCN cells ex vivowith either the proteasome inhibitor bortezomib or the selective IKKB inhibitor BMS-345541 and found them to be effective in inducing cell cycle arrest and apoptosis at relatively low dosage. By contrast, BPDCN cells turned out to be virtually insensitive to cytarabine, one of the most used drug in this condition. GEP and immunocytochemistry were then successfully used to prove that cell death was accompanied by NFkB shut-off. In conclusion, we identified a molecular signature representative of the transcriptional abnormalities of BPDCN and developed a cellular model proposing the first molecular targeted therapeutic approach in the setting of this currently incurable disease. Funding This work was supported by AIRC (IG10519 and 5xMille10007, Prof. Pileri), Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi”, BolognAIL, RFO (Prof. Pileri, Prof. Piccaluga), FIRB Futura 2011 RBFR12D1CB (Prof. Piccaluga), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006 (Prof. Pileri and Dr. Piccaluga) and by MIUR (PRIN 2011, Prof. Facchetti and Prof. Pileri). The authors have no conflicting financial interests to declare. Acknowledgments The Authors obtained the CAL-1 cell line from Takahiro Maeda (tmaeda@net.nagasaki-u.ac.jp), Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Disclosures: No relevant conflicts of interest to declare.

Vorrei iniziare con una breve premessa e poi proseguire suddividendo il mio contributo cercando di tracciare - pur in modo necessariamente essenziale - i tratti più significativi del percorso del Partito Comunista Cinese (PCC) dal 1921 al 2021in 4 parti, alla luce delle più importanti analisi e pubblicazioni emerse in questi decenni sia in Cina che fuori dalla Cina: la prima parte dedicata alle origini ed alla fondazione del PCC e a seguire le altre tre parti prendendo come punto di riferimento tre eventi e date di particolare rilevanza storicopolitica: il 1945, il 1981 e il 2021. In quegli anni, infatti, il PCC ha approvato tre documenti ufficiali (Risoluzioni) sul proprio percorso storico legati a tre fasi chiave nella riflessione sulla storia del partito: il 1945, con l’avvio del ruolo centrale e dominante di Mao Zedong; il 1981, che segna la fine dell’era maoista e fornisce un quadro di legittimazione al nuovo corso delle quattro modernizzazioni guidate da Deng Xiaping; ed infine il 2021, in novembre, con la nuova risoluzione che di fatto segna un ulteriore decisivo passo nella consacrazione storico-politica dell’attuale leader Xi Jinping. Qualunque sia la nostra percezione e valutazione del ruolo storico del Partito Comunista Cinese, dei suoi successi ed insuccessi, dei momenti più esaltanti e di quelli più drammatici, credo resti al fondo un dato: nel luglio 1921, quando venne fondato, il PCC poteva contare su di una cinquantina di membri, era un partito politico marginale composto da intellettuali che si richiamava al proletariato ma che non aveva di fatto alcun legame ed esperienza con questo. Oggi, cent’anni dopo, è un partito di oltre 90 milioni di membri che dal 1949 guida quella che oggi è la seconda potenza mondiale.

Abstract Introduction The standard treatment for elderly untreated diffuse large B-cell lymphoma (DLBCL) is RCHOP21, however up to 40% of patients experienced failures. Lenalidomide showed activity in heavily pretreated DLBCL and in vivo and in vitro data demonstrated a synergism with rituximab. In the phase I trial REAL07 (Chiappella et al, Haematol 2013), FIL demonstrated that the association of LRCHOP21 was feasible in elderly untreated DLBCL and identified 15 mg lenalidomide from day 1 to day 14 as the maximum tolerated dose in combination with RCHOP21. Patients and methods. The phase II trial REAL07 was designed based on Simon's two stage design to demonstrate an improvement of overall response rate (ORR) of 15% in LRCHOP21 compared to 70% of standard RCHOP21. Secondary endpoints were progression-free survival (PFS), overall survival (OS), event-free survival (EFS) and to correlate outcome with cell of origin (COO) profile. Response was evaluated according to 2007 Cheson criteria. Inclusion criteria were: age 60-80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; international prognostic index (IPI) at low-intermediate/intermediate-high/high (LI/IH/H) risk. Treatment plan was: RCHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. All cases were centrally reviewed by expert pathologist; COO profile analysis was conducted with immunohistochemistry according to Hans' algorithm and with gene expression profile (DASL assay). Results. From April 2010 to May 2011, 49 patients were enrolled. Clinical characteristics were: median age 69 years (range 61-80); stage III/IV 43 (88%), IPI IH/H 30 (61%). At the end of 6 LRCHOP21, ORR was 92%. Complete remissions (CR) were 42 (86%) and partial remission 3 (6%); 3 patients (6%) did not respond and one (2%) died for homicide. At a median follow-up of 28 months, 2-year OS was 92% (95% CI: 79-97), 2-year PFS was 80% (95% CI: 64-89) and 2-years EFS was 70% (95% CI: 55-81); 2-year PFS for IPI LI was 89% (95% CI: 62-97) and for IPI IH 76% (95% CI: 47-90) and for IPI H 72% (95% CI: 36-90). Hematological and extra-hematological toxicities were mild, with no grade IV extra-hematological events and no toxic deaths during treatment. Of the 294 planned courses of LRCHOP21, 277 (94%) were administered; median dose of lenalidomide delivered was 1185 mg (94% of the planned dose); at least 90% of the planned dose of each drug was administered in 91% of the RCHOP21 courses. Median interval time between RCHOP21 courses was 21 days (range 19-48). All 49 cases underwent central pathology review and diagnosis of DLBCL was confirmed. Regarding COO analysis, tissue block or stained slides were collected in 40/49 (82%), of which 32 were adequate for analysis. At the time of this abstract, COO analysis was reported according to immunohistochemistry data; DASL analysis is ongoing. Clinical characteristics between germinal center (GCB, 16 patients) and non-GCB (16 patients) were superimposable, excepted for a majority of H IPI risk in non-GCB group (p 0.067). ORR for GCB and non-GCB were 88% (CR 81%) and 88% (CR 88%), respectively. At a median follow-up of 28 months, 2-year PFS was 71% (95% CI: 40-88) in GCB-group and 2-years PFS was 81% (95% CI: 51-93) in non-GCB-group (Figure 1). Conclusions. In conclusion, LRCHOP21 is effective, also in poor risk patients, namely in non-GCB subgroup. These encouraging data warrant a future phase III randomized trial comparing LRCHOP21 vs. RCHOP21 in untreated non-GCB DLBCL. Disclosures: Off Label Use: lenalidomide in first line DLBCL is off lable. drug provided free by Celgene. Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Abstract Background. The prognostic role of cell of origin profile (COO) assessed by immunohistochemistry (IHC) is controversial in Rituximab era. FIL conducted a phase III randomized trial aimed at investigating the benefit of intensification with high dose therapy plus autotransplant compared to R-dose-dense therapy as first line in young DLBCL at poor risk (aa-IPI 2-3). Clinical results were reported (Vitolo, ASH 2012). The aim of BIO-DLCL04 was to correlate the biological markers with PFS. Patients and Methods. From 2005 to 2010, 412 untreated DLBCL at aa-IPI 2-3 were enrolled. Central histology revision was mandatory and 13 patients were excluded due to different histologies. Biological markers were analyzed on DLBCL NAS; COO analysis was performed by IHC and cases were classified in germinal center (GC) and non-GC according to Hans' algorithm; COO determined by gene expression profile using the NanoString® nCounter® Analysis System based on 20-gene assay (Lymph2Cx) using formalin fixed paraffin embedded tissue is ongoing; BCL2, BCL6 and MYC anomalies were tested by IHC; final analysis by fluorescent in situ hybridization (FISH) is ongoing. Cases were deemed positive if at least 30% of lymphoma cells were stained with each antibody (with the exception of at least 40% for MYC). Results. At the time of this analysis, 223 DLBCL NAS were analyzed: 131 non-GC and 92 GC; BCL2, BCL6 and MYC anomalies were tested in 196, 74 and 107 cases respectively. Clinical characteristics for non-GC vs GC were: median age 51 years for both, male 49% vs 45%, aa-IPI 3 15% vs 25%, bone marrow involvement (BM) 16% vs 24%. R-HDC was performed in 45% of non-GC patients and in 49% of GC. Complete response was recorded in 105 (80%) non-GC patients and in 62 (67%) GC. At a median follow-up of 49 months, the 3-year PFS for non-GC vs GC was 75% (95% CI: 67-82) vs 57% (95% CI: 46-67) with crude hazard ratio, HR 0.55 (0.35-0.87), p.01 and adjusted (for age, gender, aa-IPI, BM) aHR 0.56 (0.35-0.88), p.013. No significant differences by treatment were reported. Overexpression of MYC by IHC had a relevant prognostic impact, with aHR 1.84 (0.99-3.44), p.054. By IHC, 3-years PFS for double negative vs single BCL2 or MYC overexpression vs double positive, was 85% vs 68% vs 51% respectively, with an aHR for double expressors compared to double negative of 3.91 (1.13-13.53), p.031. At the time of the present report, FISH analysis was conducted in 88 cases: 43 were triple negative, 37 single hit and 8 double/triple hit. By FISH, 3-years PFS for triple negative vs single hit vs double/triple hit was 74% vs 84% vs 25% respectively, with an aHR for double/triple hit compared to triple negative of 5.73 (2.05 to 16.02), p.001. Conclusions. In conclusion, with the limit of the analysis performed by IHC based on Hans' algorithm, BIO-DLCL04 showed an unexpected better outcome for non-GC compared to GC, irrespective of treatment arm. The ongoing analysis conducted by Nanostring will be more informative. The overexpression of MYC was an unfavourable risk factor, mainly if associated with BCL2 overexpression, irrespective of type of treatment. Moreover, double/triple hit patients represent a subgroup with extremely poor prognosis. High dose therapy plus autotransplant was not able to reverse the inferior outcome of neither double expressors nor double hit patients and new strategies are deemed for these poor prognosis patients. Disclosures No relevant conflicts of interest to declare.

RESUMO: Neste artigo, busca-se apresentar e confirmar as seis marcas da literatura e da cultura árabe, do período do Emirado da Sicília para o nascimento da literatura italiana no Duecento, período que remete a Scuola Siciliana. Os objetivos são comprovar a inserção das seis marcas utilizadas por Ibn Hamdis, mas que a partir do processo de interculturalidade e transferência cultural, e a adoção dos seus conceitos foi possível comprovar as contribuições/heranças árabes para o nascimento da Literatura Italiana, além de refutar a hipótese de que a poesia lírica amorosa ter sido originada da Literatura Provençal, assim como, colocar a Literatura Árabe Clássica no mesmo pé de igualdade das Literaturas Clássicas: Grega e Latina para a fundação da Literatura Italiana no mapa literário.Palavras-Chave: Poesia Lírica. Poesia Sarcástica. Scuola Siciliana. Duecento. Interculturalidade. ABSTRACT: In questo articolo cerca di presentare e confermare le sei marche della Letteratura e Cultura Araba nel periodo dell’Emirato di Sicilia per il nascimento della Letteratura Italiana nel Duecento, periodo che fa riferimento alla Scuola Siciliana. Gli obbiettivi sono verificare le inserzioni delle sei marche usati per Ibn Hamdis, ma che attraverso del processo d’interculturalità e di trasferimento culturale ed adozione dei suoi concetti fu possibile dimostrare i contributi arabi per il nascimento della Letteratura Italiana, oltre di rifiutare l’ipotesi di che la poesia lirica amorosa fu originata della Letteratura Provenzale, così come a mettere la Letteratura Classica Araba nella stessa egualità delle Letterature Classiche: Greca e Latina per la fondazione della Letteratura Italiana nel cammino letterario.Parole-Chiave: Poesia Lirica. Poesia Sarcastica. Scuola Siciliana. Duecento. Interculturalità. ABSTRACT: In this article, we will intend to present and confirm the six signatures of Arab literature and culture, from the Sicily emirate to the birth of the Italian Literature during the Duecento, the age of Scuola Siciliana. Our main goal is to prove the insertion of the six signatures used by Ibn Hamdis. Through the process of interculturality and cultural transfer as well as the adoption of his concepts, it was possible to inform the Arab contributions and heritages tot the birth of Italian literature; on the other side, we want to refute the hypothesis that the lyric poetry had its origin in the Provençal poetry. Furthermore, we intend to match the Classical Arab literature with Greek and Latin literatures regarding of the foundation of Italian literature in the studies of literature.Keywords: Lyric poetry. Satirical poetry. Scuola Siciliana. Duecento. interculturality.

The introduction in equine reproduction of ovum pickup (OPU) combined with intracytoplasmic sperm injection (ICSI), IVC, and embryo transfer, has allowed for the production of offspring from donors and stallions that could not reproduce by conventional techniques. For this reason, we used in our OPU-ICSI-IVC program both fertile stallions and stallions with field records of low or no fertility. Overall, 805 and 584 OPU oocytes were fertilized with sperm from fertile and infertile stallions, respectively. Cleavage rate was statistically lower in the latter group (65.94 v. 59.24%, chi square test; P < 0.05) but embryo development was similar (11.67 v. 8.20% blastocysts/injected oocytes, chi-square test). In order to further investigate the stallion effect on embryo development, we selected 3 stallions with low (A) or no (B, C) fertility in the field and we compared the results of the OPU program with embryo development obtained using oocytes recovered from abattoir ovaries and matured, fertilized, and cultured in vitro as the OPU oocytes. Part of the abattoir oocytes was fertilized with a stallion with known high fertility both in vivo and in vitro (abattoir fertile). Overall, the results (shown in the table) suggest a reduction in the efficiency of stallions A, B, and C compared with to the fertile stallion used as control (10.79, 7.69, and 5.0% v. 17.35%, respectively). For stallions A and B, the efficiency was further reduced in the OPU setting, indicating that the female component can play a role in the overall efficiency of the procedure. In particular, 4 mares out of 8 had a history of no pregnancy and all mares had some rate of inbreeding with the respective stallion used for the ICSI. Instead, the oocytes from the abattoir ovaries were collected in large pools from several mares, representing an average oocyte quality, and the mares were of different breed than the stallions. All data were analyzed by chi-square test and significance was set at P < 0.05. In conclusion, we demonstrated that, for those stallions in which fertility in the field is low or absent, OPU-ICSI-IVP is a suitable choice to obtain embryos, although the efficiency is variable depending not only on the stallion but also on the origin of the oocytes. Table 1.Stallion effect on embryo development of ovum pickup (OPU) and abattoir oocytes This work was supported by Fondazione Cariplo and Regione Lombardia.

Abstract Abstract 3399 The oncogenic transformation of Chronic Myeloid Leukemia (CML) cell of origin has been associated to an increased glucose metabolism, where the glycolytic pyruvate is directed away from the mitocondria, converted into lactate and secreted from the cell. This metabolic conversion is termed aerobic glycolysis, or Warburg effect and very essentially, it serves to support the tumor cell proliferation, by providing nucleotides, aminoacids and lipids enough to replicate all of cellular content. CML patients are historically stratified according to their Sokal risk score, which for more than 30 years has been regarded as the most significant prognostic factor in this hematological malignancies. The putative genetic and/or genomic basis driving this stratification are still not known. Aim of the present study was to explore the molecular mechanisms associated to the CML patients stratification according to the Sokal risk score, by analyzing the transcriptome of the CD34+ cell fractions obtained at diagnosis from a cohort of high and non-high Sokal risk CML patients. Overall, 67 patients with previously untreated CML in chronic phase (CP) entered the study; all of them have been enrolled in GIMEMA CML protocols and provided highly enriched CD34+ cell fractions from peripheral blood. Gene expression profiling (GEP) was performed, in order to identify genes most significantly and most differentially expressed between high and non-high Sokal risk patients. All other cases were used in Real-time experiments, in order to validate the GEP data. By GEP, 82 probe-sets, corresponding to 78 genes resulted significantly differentially expressed between high and non-high Sokal risk patients in a supervised analysis of gene profiles. A gene enrichment analysis of this profile showed that genes involved in the Wnt, in the Notch signaling pathways and in the response to hypoxia and oxidative stress resulted significantly overexpressed in the comparison between high and non-high risk patients. We focused our attention on genes involved in the glycolysis and gluconeogenesis metabolic pathways (FBP1, SEPP1, GSTM3, GSTT1, PRDX2, MPO). We validated by Real-time the de-regulated expression of these genes in a different set of newly diagnosed CP-CML patients, thus confirming that they are differentially expressed between high and non-high risk patients, with trends similar to those observed by GEP. Particularly interesting resulted a significantly higher expression in high Sokal risk patients of FBP1 (fructose 1,6 bisphosphatase), a key-enzyme of gluconeogenesis, together with a significant over-expression of genes coding for enzyme involved in gluthatione biosynthesis (GSTM3, GSTT1, and PRDX2). These data suggest that CD34+ cells obtained from high Sokal risk patients might exhibit an unexpected moderation of the glycolytic flux, mainly due to the over-expression of FBP1, which might cause a re-direction of the pathway into the pentose phosphate shunt. A similar metabolic reprogramming has been already described in imatinib resistant bcr-abl positive cell lines and is supported also by the over-expression in high risk patients of G6PDH (Glucose-6-phosphate 1-dehydrogenase) and TK (Transketolase), which are key enzyme of the pentose phosphate shunt. Overall, our data demonstrate for the first time, that the expression at diagnosis of sugar metabolic enzymes, might drive the evolutive Sokal risk of CML patients. Supported by: European LeukemiaNet, BolognAIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integrate program (PIO), Programma di Ricerca Regione – Università 2007 – 2009. Disclosures: Rosti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy.

Abstract Abstract 3580 Introduction: Although treatment with tyrosine kinase inhibitors (TKIs) has revolutionized the management of adult patients with BCR-ABL1 -positive acute lymphoblastic leukemia (ALL) and significantly improved response rates, relapse is still an expected and early event in the majority of them. It is usually attributed to the emergence of resistant clones with mutations in BCR-ABL1 kinase domain or to BCR-ABL1 -independent pathways but many questions remain unresolved about the genetic abnormalities responsible for relapse after TKI and chemotherapy-based regimens. Patients and methods: In an attempt to better understand the genetic mechanisms responsible for this phenomenon, we have analyzed matched diagnosis-relapse samples from 30 adult BCR-ABL1 -positive ALL patients using high resolution Affymetrix single nucleotide polymorphism (SNP) arrays (GeneChip® Human Mapping 250K NspI, n=15 pairs and Genome-Wide Human SNP 6.0, n= 15 pairs). Genetic differences were analyzed in terms of copy number changes and loss of heterozygosity (LOH) events. 20 patients were enrolled in clinical trials of GIMEMA AL Working Party and treated with imatinib alone or in combination with conventional chemotherapy (40%) or dasatinib as frontline therapy (60%). The median age at diagnosis was 54 years (range 23–74) and the median blast cell count was 97% (range 60–99). The median time to relapse was 27 months (range, 9–104). 10 patients were treated according to the GMALL trials, a high-dose chemotherapy based protocol in combination with imatinib. The median age at diagnosis was 65 years (range 19–79) and the median leucocyte count was 37300/μl (range 5000 – 220000/μl). The median time to relapse was 9.8 months (range, 3 – 25). Results: First, we compared diagnosis and relapse samples for the presence of macroscopic (> 1.5 MB) copy number alterations (CNA). Novel acquired macroscopic CNAs were detected in 7/20 (35%) TKI relapse cases and included losses of 3p12-p14, 5q34, 9q34, 10q24 and 12p13-p12 and gains of 1q, 9q34-q33 and 22q and in 4/10 (40%) chemotherapy-relapse cases and included losses of 9p21 and 12q21–22 and gains of all chromosome 8 or part of it in 2 patients. Since no common patterns of acquired alterations were observed, it is likely that relapse may be due to a more generalized genetic instability rather than to specific mechanisms. Moreover, chemotherapy did not select resistant clones with higher number of alterations. 8/20 (40%) TKI resistant cases and 4/10 chemotherapy resistant patients harbored the same CNAs present in the matched diagnosis sample (losses of 9p21 in 7 cases, 7p and 22q11 in single cases and gains of chromosomes 1q, 4, 8q, 17q and 21), indicating a common clonal origin. In contrast, in 5/20 (25%) TKI resistant cases and 4/10 (40%) chemotherapy resistant patients macroscopic CNAs present at diagnosis were lost at relapse (losses of chromosomes 7, 11q, 14q, 15q, 16q and 19p and gains of 5q, 8q, 9q34 and 22q11). Thereafter, we compared diagnosis and relapse samples for microscopic CNAs (< 1.5 MB). The alteration most frequently acquired at relapse was loss of the tumor suppressor CDKN2A (53% vs 33 % of diagnosis). Other common acquired CNAs at relapse included gains of ABC transporter genes, such as ABCC1, ABCC6 (1q41) and BCL8 (15q11); losses affected EBF1 (5q33) and IGLL3 (22q11) genes involved in B-cell development, BTG1 (12q21) involved in cell cycle regulation and CHEK2 (22q12) involved in DNA repair. Interestingly, for all relapse cases analysis of IKZF1 deletions, identified in 80% of patients, demonstrated a clonal relationship between diagnostic and relapse samples, suggesting that this alteration is not acquired with relapse but it is maintained with fidelity from diagnosis working as a marker of disease. The majority (92%) of relapse samples harbored at least some of the CNAs present in the matched diagnosis sample, indicating a common clonal origin. Conclusions: Genomic copy number changes evolving from diagnosis to relapse have been identified demonstrating that a diversity of alterations contributes to relapse and with the most common alterations targeting key regulators of tumor suppression, cell cycle control, and lymphoid/B cell development. Supported by European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2009, Ateneo RFO grants, PIO program, Programma di Ricerca Regione – Università 2007 – 2009. Disclosures: Soverini: Novartis: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy. Baccarani:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy; Novartis: Research Funding; Pfizer Oncology: Honoraria; Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Ottmann:Novartis Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy.

Background. The outcome of relapsed/refractory diffuse large-B cell lymphoma (DLBCL) patients after first line chemoimmunotherapy is poor, and the choice of the best salvage treatment is challenging. Acisplatin-containing regimen (DHAP, cisplatin, high-dose citarabine, dexamethasone) is worldwide accepted as induction pre-stem cell transplantation (SCT). Bortezomib had proven activity in aggressive lymphomas. On these bases, the Fondazione Italiana Linfomi designed the FIL-VERAL12 trial, aimed at evaluating whether the addition of bortezomib to rituximab-DHAP (BR-DHAP) increases complete response rate (CR, according to Lugano 2007 criteria) prior SCT compared to standard R-DHAP. Methods. FIL-VERAL12 was a prospective, multicenter, two-arm randomized phase II trial (NCT01805557).The primary study endpoint wasCR after 4 courses of R-DHAP or BR-DHAP, assuming a 30% CR for the standard arm and a 50% CR in experimental arm. Inclusion criteria were: patients aged 18-65 years with relapsed/refractory DLBCL after first line chemoimmunotherapy, eligible to high-dose therapy. A centrally histological review and classification according to cell of origin profile was planned. Patients were stratified by relapsed or refractory and randomized 1:1 to receive: a) the standard salvage therapy R-DHAP every 28 days for 4 cycles and b) subcutaneous 1.5 mg/sqm bortezomib on days 1 and 4 of each 4-week cycle in addition to the same regimen. Restaging, mobilization and harvesting of peripheral stem cell were performed after the second course. Results. From January 2013 to November 2018, 114 patients were screened; 108 eligible patients were enrolled into the trial and randomized to receive R-DHAP or BR-DHAP (54 patients in each arm). Principal clinical characteristics were: median age 57 years (IQR: 48;62); stage III/IV 81 patients (75%); IPI risk >3 32 (30%). All patients received rituximab and anthracycline-based regimens as first line treatment. Considering the time at relapse, 52 patients (48%) were registered as relapsed (median time at relapse 10.8 months, IQR: 6.9;20.9) and 46 (43%) as refractory (0.9 months, IQR 0.52;1.3); in the remaining 10 patients the data is missing at the time of this analysis. 51 (47%) patients completed the planned 4 cycles of therapy; 57 did not, due to progressive disease in 20, adverse events in 2, unknown causes in 35 cases. Intermediate response after 2 courses was: CR 16 (15%), partial response (PR) 37 (34%), stable disease (SD) 16 (15%); 24 (22%) were in progression (PD) and 15 (14%) were not available for response. At the end of treatment, the pre-ASCT response was: : CR 30 (28%), PR 10 (9%), SD 13 (12%), PD 38 (35%), NA 17 (16%). According to arm of randomization, the primary end point was not met, with CR 30% for R-DHAP and 26% for BR-DHAP (Pr 0.667). 38 patients performed a consolidation SCT, autologous SCT in 38, allogeneic SCT in 4. The addition of bortezomib to standard R-DHAP did not impact the mobilization: only one patient was poor mobilizer and the median number of CD34+ collected was 6.9 x 10^6 cells CD34/kg (IQR: 4.8; 9.7), with no differences between the two arms. No toxic deaths were recorded into the trial. On 294 cycles with data available, haematological and extra-haematological toxicities were: grade 3-4 neutropenia in 152 of 294 courses (52%), g 3-4 thrombocytopenia in 209 (71%); g 3-4 febrile neutropenia in 4 (1%), g3-4 infection in 5 (2%), g3-4 neurotoxicity in 5 (2%); the incidence of adverse events were similar in the two arms. At a median follow-up of 9.8 months, 12-months PFS was: overall 48.8% (38.4-58.4), 44.6% (30.4-57.8) and 53.1% (37.9-66.1) for R-DHAP and BR-DHAP, respectively (log rank, p 0.464). At a median follow-up of 15.9 months, 12-months OS was: overall 69% (58.2-77.7), 62.7% (46.4-75.3) and 75.1% (59.6-85.4) for R-DHAP and BR-DHAP, respectively (log rank, p 0.628). Conclusions. In the FIL-VERAL12 phase II randomized trial, the addition of bortezomib to R-DHAP did not improve the outcome of relapsed/refractory DLBCL patients eligible to high-dose therapy plus SCT. This series of patients is mainly represented by true refractory patients after first line chemoimmunotherapy and the results underline the poor outcome of such patients. The treatment for these patients is still an unmet clinical need. The role of immunotherapies such as the integration of CAR-T therapy in this setting of patients should be investigated. Disclosures Chiappella: Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau. Corradini:Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Servier: Honoraria; KiowaKirin: Honoraria; Sanofi: Honoraria; Gilead: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Takeda: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Nassi:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: the use of subcutaneous bortezomib is not registered in diffuse large B-cell lymphoma. Bortezomib was provided free by Janssen

Abstract Abstract 1027 Poster Board I-49 Background: Current therapeutic strategies for the treatment of elderly acute myeloid leukemia (AML) patients are still unsatisfactory. Induction regimens relying on anthracycline and cytarabine combination (3+7) still represent the standard reference therapy, with complete remission (CR) rate of 35-60% but no more than 10-20% of patients living more than three years from diagnosis. The addition of other drugs to overcome resistance and prevent subsequent relapse, has often shown greater toxicity without improving results. Aim We designed a phase II study aiming to assess toxicity and efficacy of My-FLAI regimen in patients with newly diagnosed AML aged more than 60 years. Fifty-one patients were enrolled with a median age of 68 years (range 60-76). The median leukocyte count was 10.2 ×109/L (range 0.7-222.7). Twenty-five patients had a secondary AML and 31% had a complex kariotype. Fludarabine, cytarabine and idarubicin were administered for three consecutive days at the daily dose of 25 mg/m2, 1 g/ m2 and 5 mg/ m2 respectively. Gemtuzumab ozogamycin (Mylotarg, My) was infused at day four at the dose of 5 mg. Patients achieving a CR after the induction course were planned to receive a second identical course of My-FLAI. Granulocyte colony-stimulating factor (G-CSF) was administered at physician's discretion to promote granulocytic recovery if clinically indicated. Results: Twenty-seven patients achieved a CR (one of these with an incomplete platelet recovery) and 4 obtained a partial response (marrow blast 5-19%) for an overall response rate (ORR) of 61%. Seventeen patients (33%) showed a resistant disease and three (6%) died during induction (DDI). Seventeen patients received an identical consolidation course. Seven patients were treated with cytarabine-based consolidation and the remaining 27 patients were not treated furthermore. The disease-free survival (DFS) and overall survival (OS) were 6 months (range 2.4-48.0) and 13 months (range 1.1-61.5) respectively. DFS appear to be more favorable in patients receiving additional therapy after two My-FLAI cycles (IDAC n=3; ASCT n= 4; experimental drugs n= 1; My n=4) in comparison to patients no further treated, being 12.8 (range 4.7-18.0) and 5.9 (range 2.4-48.0) months respectively. The median duration of G-CSF administration was 6 days (range 0-35) in induction and 8 days (range 0-15) in consolidation cycle. All patients developed a grade IV hematological toxicity. Median time to ANC recovery (>1 ×109/L) was 21 days (range 10-52) after induction course and 18 days (range 12-20) after consolidation course. Median time to PLT recovery (PLT>20 ×109/L and PLT>100 ×109/L) was 18 days (range 9-54) and 23 days (range 15-78) after induction and 18 days (range 12-20) and 32 days (range 21-110) after the consolidation course. Thirty-six patients had infectious complication; 33 experienced a microbiologically documented infection (n=20 gram+, n=12 gram- n=1 candidemia). Eighteen patients had a fever of unknown origin (FUO) and 12 patients suffered from pulmonary infection (n=2 bacterial; n=8 probable fungal; n=2 aspergillosis). One patient developed a maxillary sinus aspergillosis. Grade III/IV haemorrhagic complications were observed in 5 patients. No severe gastro-intestinal adverse events were observed. With a median follow-up of 8.8 months (range 0.5-61.5) 41 patients died. Five patients died in first CR for cardiac failure (n=2) and for infective complication (n=3). The remaining died for disease. Nine patients are alive, four of them in first CR. Conclusions: The four drug regimen My-FLAI is overall well tolerated in an elderly AML population. However, the efficacy did not appear to be superior to that of standard “3+7” regimen. Acknowledgments: Supported by BolognAIL, AIRC, European LeukemiaNET, COFIN, FIRB 2006, Fondazione del Monte di Bologna e Ravenna Disclosures: No relevant conflicts of interest to declare.

Background:High-resolution computed tomography (HRCT) is the gold standard diagnostic test for Interstitial lung disease (ILD), a significant cause of morbidity and mortality in systemic sclerosis (SSc). Different algorithms have been proposed for the screening of SSc-ILD, including the use of pulmonary function tests (Forced Vital Capacity - FVC, Lung Diffusion of Carbone Monoxyde - DLCO). A prior survey reported that 50-66% of general rheumatologists and SSc experts ordered HRCT for ILD screening in newly diagnosed SSc patients (1).Objectives:Given the recent availability of on-label treatment for SSc-ILD (2), the publication of consensus recommendations for the identification of SSc-ILD (3) and recent awareness programs for the use of HRCT to detect SSc-ILD, we aimed to re-evaluate the use of HRCT for screening, re-screening and follow-up of SSc-ILD.Methods:An invitation was sent to the European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members, also advertised through social media. Answers were recorded between Nov 25th and Dec 31st 2020. Questions were asked on the use of chest HRCT at baseline, the re-screening of patients with a negative baseline HRCT and the follow-up of HRCT positive SSc-ILD patients. When HRCT was not routinely requested, additional details were collected about the parameters guiding its use. The results of the survey were tested for association with geographical origin, medical specialty, working environment, SSc referral institute and scientific group membership of the responders, using Chi-squared test.Results:205/630 (32.5%) physicians replied to the survey. Participants were widely distributed in terms of geographical origin (130 Europe, 23 Asia, 23 North America, 31 other continents), medical specialty (156 rheumatology, 21 internal medicine, 14 clinical immunology, 14 other), working environment (176 University Hospital, 12 community hospital, 17 other), SSc dedicated clinic (179 referral and 26 non-referral) and scientific group membership (98 EUSTAR, 42 SCTC, 42 EUSTAR and SCTC, 23 not declared).At SSc diagnosis, 95.7% of responders would perform HRCT: 66.7% as routine screening for ILD (67,4% of SSc referral and 62% for non-referral physicians) and 29% for diagnostic purposes (among the latter, if crackles on auscultation – 92.5%, FVC<80% predicted - 86.6%, FVC±DLCO relative decline reaching the current definition of ILD progression, 86.6% or dyspnea at rest/exercise - 85.1/83.3%).During follow-up, 78.8% of responders would repeat an HRCT in baseline negative cases: 20.3% as a yearly routine screening and 64.5% for diagnostic aims (decision on the latter group was more frequently driven by FVC±DLCO relative decline indicative of ILD progression– 90.6%, new onset or worsening of dyspnoea at rest/exercise – 80.5/86.6%, new onset or worsening of lung crackles on auscultation – 82.6%).Finally, 94.5% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.8% as a yearly routine and 56.7% according to clinical evaluation (driven by new FVC±DLCO relative decline based ILD progression – 90.8%, new onset or worsening of dyspnoea at rest/exercise – 83.2/81.7%; 5.2% to evaluate treatment effects). We found no difference in the distribution of answers among groups.Conclusion:The use of baseline HRCT for the screening of SSc-ILD has slightly increased in non-referral and remained stable in referral centers compared to previous surveys, indicating that the implementation of guidelines might be successful and awareness programs should be continued. In addition, we provide new data on use of HRCT in re-screening and follow-up. The development of validated algorithms to further support the appropriate application of HRCT at follow-up is highly needed.References:[1]Bernstein EJ et al. Arthritis Rheumatol. 2018 Jun;70(6):971-972.[2]Distler O et al. N Engl J Med. 2019 Jun 27;380(26):2518-2528.[3]Hoffmann-Vold AM et al. The Lancet Rheumatology, Volume 2, Issue 2, e71 - e83.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Sclerodermia Trial and Reserach (EUSTAR) Group., Lorinda Chung Consultant of: Boehringer Ingelheim, Eicos, Mitsubishi Tanabe, Reata., Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX therapeutics, Bayer, Boehringer-Ingelheim, Medscape, MSD, Lilly, Roche, Shervin Assassi Speakers bureau: Integrity Continuing Education, Consultant of: Boehringer Ingelheim, Novartis, and Corbus, Armando Gabrielli: None declared, Dinesh Khanna Consultant of: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics Leadership, Grant/research support from: NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Equity position – Chief Medical Officer, Eicos Sciences, Inc., Elana Bernstein Consultant of: Boehringer Ingelheim, Oliver Distler Consultant of: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB., Grant/research support from: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143).

Abstract Introduction: thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy, with a reported incidence of 2-6 cases/million/year and a 10-20% mortality. TTP is associated with the severe deficiency of the von Willebrand factor cleaving protease, ADAMTS13, due to congenital defects in the ADAMTS13 gene (congenital TTP) or to the development of autoantibodies against ADAMTS13. The Milan TTP Registry is a digital database developed and curated at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy), including demographic, clinical and laboratory data of patients with a confirmed diagnosis of congenital or acquired thrombotic thrombocytopenic purpura (TTP). Aims: to report the natural history of patients affected with acquired TTP enrolled in the Milan TTP Registry, including demographic, clinical and laboratory data. Methods: acquired TTP patients enrolled in the Milan TTP Registry for an acute episode of TTP occurred between January 2002 and November 2015, and followed until May 2016, were included in this study. Acquired TTP was defined as the occurrence of thrombocytopenia and microangiopathic hemolytic anemia, in the absence of alternative causes. Patients with acquired TTP secondary to cancer and bone-marrow transplant were excluded from this analysis. Demographic and disease-related information were collected by a standardized clinical questionnaire. ADAMTS13-related measurements were performed in a centralized laboratory in Milan. Remission of an acute TTP episode was defined as two days after normalization of the platelet count (≥150 x 109/l). Results: 416 patients with a confirmed diagnosis of acquired TTP were included in the Milan TTP Registry, for a total of 837 acute events. Demographic, clinical and laboratory data are reported in Tables 1 and 2. The majority of patients were female (77%), of white ethnicity (98%) and Italian origin (82%). The median age at the first TTP episode was 40 years (interquartile range [IQR] 30-52). A history of other autoimmune diseases, cancer (non-active at the time of the TTP event), HIV infection and other diseases such as stroke, acute myocardial infarction and hypertension was reported in 34% of the patients. Among potential triggers of acute episodes (defined as occurring within three months before onset), infections were the most prevalent (22% of all patients), followed by the assumption of estroprogestinic drugs (5%). At TTP episode onset, systemic, bleeding and neurological signs and symptoms were present in 70%, 68% and 44% of acute events, respectively, whereas a lower prevalence of renal (19%) and cardiovascular (10%) signs and symptoms was observed. Clinical characteristics and hematologic laboratory parameters were less severe in relapsing episodes compared with first episodes (Table 2). Almost all acute events were treated by plasma exchange procedures and steroids. Rituximab therapy was administered in 12% of acute TTP episodes. In 197 acute TTP episodes with available ADAMTS13-related measurements at baseline, ADAMTS13 activity was severely reduced (<10%) in 85%, moderately reduced (10% to lower limit of normal range) in 12% and normal in 3% of events, respectively. Anti-ADAMTS13 antibodies were positive in 93% of acute TTP. The TTP-related mortality in our population of acquired TTP patients was 5%. In survivors, the median time to remission was 13 days (IQR 7-24, n=313), shorter for relapses than first events (median difference 8 days, 95% confidence interval 5-11). In 348 patients who survived the first TTP episode and had a follow-up period of at least 6 months, 178 (51%) experienced only one episode of acquired TTP, whereas 170 (49%) developed a recurrent form of the disease. This results might be overestimated due to the tertiary nature of our center. Conclusions: acquired TTP is a rare, potentially fatal disease, which may require a long hospitalization and presents in a recurrent form in nearly half of the patients. Digital registries, such as the Milan TTP Registry, represent a powerful and necessary tool to systematically collect epidemiologic, clinical and laboratory data which may ultimately improve our understanding and management of acquired TTP. Our registry, in collaboration with those of other international centers, might answer the most relevant questions in this field. Disclosures Peyvandi: Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau; SOBI: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Bayer: Speakers Bureau; Grifols: Speakers Bureau; LFB: Consultancy; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding.

A painting of the Virgin and Child, signed as “OPVUS P. PETRI”, from the former Fareham Collection (today at the Courtauld Institute of Art), has been known in the scholarly literature for a long time but has only been subject to tangential analyses. These studies attempted to attribute it to painters meeting relatively dubious criteria: that their name was Peter (Petar) and that they could be linked to the painting circle of Squarcione or, more specifically, to that of Carlo Crivelli with whose early works, especially the Virgin and Child (the Huldschinsky Madonna) at the Fine Arts Gallery in San Diego, the Courtauld painting shares obvious connections. Roberto Longhi ascribed it to the Paduan painter Pietro Calzetta in 1926, while Franz Drey, in 1929, considered it to be the work of Pietro Alemanno, Crivelli’s disciple, who worked in the Marche region during the last quarter of the fifteenth century. After the Second World War, the Courtauld painting was almost completely ignored by the experts. The only serious judgement was that expressed by Pietro Zampetti, who established that it was an almost exact copy of Crivelli’s Huldschinsky Madonna, meaning that if Calzetti had painted it, he would have done it while Carlo was still in the Veneto, before he went to Zadar.The search for information which can shed more light on the attribution of the Virgin and Child from the Courtauld is aided by the valuable records in the Fondazione Federico Zeri at the Università di Bologna. The holdings of the Fototeca Zeri include three different photographs of the Courtauld painting with brief but useful accompanying notes. Of particular importance is the intriguing inscription on the back of one of the photographs, which points to the painting’s Dalmatian origin. In a certain way, this opens the possibility that it might be linked to another painter who was close to the Crivelli brothers: the Zadar priest and painter Petar Jordanić. That he may have been the one who painted it is indicated by the signature itself, which could be read as “OPVUS P(RESBITERI) PETRI”.Archival records about Petar Jordanić provide almost no information about his work as a painter. Apart from his signature of 1493 on a no-longer extant polyptich from the Church of St Mary at Zadar, the only record of his artistic activities is one piece of information: that in 1500 he took part in a delegation which was sent from Zadar to its hinterland charged with the task of making drawings of the terrain which could be used to help defend the town against the Ottoman Turks. However, more than thirty documents which mention him do paint a picture of his life’s journey and his connection with Zadar. The most important basis for any consideration of a possible connection between Petar Jordanić and Carlo Crivelli can be found in the will of his father Marko Jordanov Nozdronja (in late 1468) where Petar was named as the executor, meaning that at this point he was of age. Therefore, it can be concluded that he was born between 1446 and 1448. This makes him old enough to have been taught by Carlo during his stay in Zadar from c. 1460 to 1466. Although relatively modest, the oeuvre of Petar Jordanić demonstrates striking connections with the paintings of Carlo and Vittore Crivelli, and Ivo Petricioli has already put forward a hypothesis that he may have been taught by one of the brothers.The comparison between the painting from the Courtauld Institute of Art in London and the known works of Petar Jordanić (the Virgin and Child from a private collection in Vienna; the Virgin and Child from the Parish Church at Tkon; fragments of a painted ceiling from Zadar Cathedral; the lost polyptich from the Church of St Mary at Zadar) reveals a multitude of similar features. Apart from the general resemblance in the physiognomies of the Virgin and Christ Child which represent the most conspicuous analogies, a number of very specific “Morellian” elements can also be noted in the manner in which the faces were painted. These similarities are particularly apparent when one compares the head of the Christ Child on the painting from London and his head on the one from Tkon, which are almost identically depicted. Further similarities between the London painting and the one at Vienna can be seen in the way in which landscapes were painted and in the similar decorations of the gold fabrics in the backgrounds with their undulating scrolls and sharp almond-shaped leaves.However, with regard to visual characteristics, it is apparent at first sight that the quality of the London painting is markedly higher and that it is stylistically more advanced than those works which are attributed with certainty to Jordanić. These differences can be explained by the possibility that this was a more or less direct copy of one of Carlo Crivelli’s painting, probably not the Huldschinsky Madonna but one that was very similar to it and subsequently lost.Naturally, if the London painting is attributed to Petar Jordanić, meaning that it was produced in Zadar, then the argument on the basis of which the Huldschinsky Madonna has been dated to the time before Crivelli’s arrival in Zadar becomes a counter-argument, and, in that way, corroborates the possibility that the Huldschinsky Madonna, which shares a large number of similar elements with the painting from the Courtauld Institute of Art, was created while Carlo was in Zadar.

Abstract Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Advanced age is an important adverse feature in prognostic models, and nearly one third of cases occur in patients older than 75 years. There is no clear accepted standard of care for older patients with DLBCL due to under-representation of this group in randomized clinical trials. R-miniCHOP, a dose attenuated version of standard R-CHOP, is often chosen based on a prospective, single-arm phase II trial which showed a 2-year progression-free survival (PFS) of 47% (Peyrade, 2011), far lower than observed outcomes in patients younger than 80 yrs (Coiffier, 2002). Precise identification of older DLBCL patients who should be considered for curative versus palliative chemoimmunotherapy is difficult at an individual level; the challenge is to avoid both overtreatment with excessive toxicity and undertreatment with inferior outcomes. The FIL (Fondazione Italiana Linfomi; Italian Lymphoma Foundation) has developed an assessment tool accounting for age, comorbidities, and ability to perform activities of daily living (ADLs) and instrumental activities of living (IADLs). The FIL Tool classifies patients as "fit," "unfit," or "frail." When the FIL tool was prospectively applied to 1163 patients, 55% were fit, 28% were unfit, and 18% were frail. Three-year OS for the whole cohort was 65% and was strongly driven by fitness: 3-year OS was 75% for fit patients, 58% for unfit, and 43% for frail; similar outcomes were seen in a validation cohort (Merli F, 2021). However, treatment was not uniformly directed and was up to the treating physician. Epigenetic deregulation is a feature of DLBCL in older patients, and provides a rationale for targeting methylation. Pre-clinical models show that pre-treatment with hypomethylating agents improves the anti-tumor effect of R-CHOP (Clozel T, 2013). This work has led to early clinical studies of the hypomethylating agent azacitidine with R-CHOP in newly diagnosed DLBCL, with promising early efficacy and acceptable toxicity. The availability of oral azacitidine is an appealing additive approach and is agnostic to cell-of-origin. Based upon the need for improved outcomes in older patients and the promise of azacitidine in this setting, the National Clinical Trials Network (NCTN), led by SWOG, developed S1918, a randomized trial comparing R-miniCHOP to R-miniCHOP + oral azacitidine for older patients (&gt; age 75) with newly diagnosed aggressive B-cell non-Hodgkin lymphomas. This study incorporates the FIL Tool for baseline frailty assessment and a serial comprehensive geriatric assessment (CGA) to evaluate effects of therapy on quality of life and functional status. This is the first randomized study in this population conducted in North America by the NCTN and will enroll a total of 384 eligible patients after a safety run-in phase. All patients will receive pre-phase therapy with vincristine 1mg x 1 and prednisone 60mg/m2 x 7 days (capped at 100mg/day); pre-phase therapy has been shown to improve performance status and decrease early treatment-related mortality (Owens CN, 2015). The primary objective of the phase II component is to determine if oral azacitidine + R-miniCHOP regimen should be tested further (Phase III) against R-miniCHOP alone based on estimates of 1-year progression-free survival (PFS). The primary objective of the phase III component is to compare the OS at 2 years between oral azacitidine + R-miniCHOP and R-miniCHOP alone. Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma in a number of ways given its randomized design, incorporation of geriatric assessments, and utilization of ctDNA correlatives. The prospective assessment of frailty, serial comprehensive geriatric assessments, and introduction of epigenetic modulation will hopefully improve outcomes for this population with significant need. Trial registration: ClinicalTrial.gov Identifier NCT04799275 Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, and U10CA180821 Figure 1 Figure 1. Disclosures Brem: Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Consultancy; SeaGen: Speakers Bureau; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees. Caimi: Seattle Genetics: Consultancy; Verastem: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); Amgen Therapeutics.: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy; ADC Theraputics: Consultancy, Research Funding; TG Therapeutics: Honoraria. Cerchietti: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Alizadeh: Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Bristol Myers Squibb: Research Funding. Olin: Amgen: Honoraria; Cellectis: Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Abbvie: Honoraria; Actinium: Honoraria; Astellas: Honoraria, Research Funding. Friedberg: Novartis: Other: DSMC ; Bayer: Other: DSMC ; Acerta: Other: DSMC . Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator.

Abstract Background: Rituximab (R) plus CHOP (R-CHOP) is standard-of-care treatment for previously untreated diffuse large B-cell lymphoma (DLBCL). Approximately 35-40% of patients (pts) will relapse following R-CHOP, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; GAZYVA/GAZYVARO; G) is a glycoengineered, type II anti-CD20 monoclonal antibody with greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R. In the Phase 2 GATHER study (NCT01414855), G plus CHOP (G-CHOP) demonstrated manageable toxicity and promising efficacy in pts with advanced untreated DLBCL. GOYA (NCT01287741) is an open-label, multicenter, randomized Phase 3 study comparing the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. GOYA was sponsored by Roche with scientific support from the Fondazione Italiana Linfomi. Methods: Eligible pts were aged ≥18 years and had adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status (PS) of ≤2 and an International Prognostic Index (IPI) score of ≥2 (high, high-intermediate or low-intermediate risk). Low-risk pts with an IPI score of 1 (but not due to age alone) or with an IPI score of 0 with bulky disease (one lesion ≥7.5cm) were also eligible. Pts were randomized 1:1 to receive 8 (21-day) cycles of G (1000mg i.v. on Days [D] 1, 8, and 15, Cycle [C] 1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP (number of cycles preplanned in advance for all pts at each site). Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS); for the target hazard ratio (HR) of 0.75, the 3-year PFS was expected to improve from 60% to 68%. Secondary endpoints included: PFS assessed by Independent Review Committee (IRC); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (assessed by INV or IRC according to modified Cheson 2007 criteria); and safety. Results: 1418 pts were randomized to study treatment: 706 to G-CHOP and 712 to R-CHOP. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms: mean age, 62.0 years in both arms; ECOG PS ≥2, 12% vs. 14%; IPI score ≥3, 47% vs. 43%; Ann Arbor stage III-IV, 76% in both arms. Cell-of-origin distribution, as assessed by gene-expression profiling (NanoString), was similar in both treatment groups (GCB: 58% [271/471] G-CHOP, 58% [269/462] R-CHOP; ABC: 27% [125/471] G-CHOP, 26% [118/462] R-CHOP; Unclassified: 15.9% [75/471] G-CHOP, 16.2% [75/462] R-CHOP). For the primary endpoint of INV-assessed PFS, there was no significant difference between G-CHOP and R-CHOP (3-year PFS, 69% vs. 66%; stratified HR, 0.92; 95% confidence interval [CI], 0.76, 1.12; p=0.3868; Table). Secondary endpoints, including PFS by IRC, OS, and end-of-treatment ORR/CR rate (with and without PET), were consistent with the primary endpoint, with no clinically meaningful differences observed between the treatment arms (Table). In a prespecified subgroup analysis of INV-assessed PFS, a stratified HR of 0.72 (95% CI, 0.50, 1.01) in favor of G-CHOP over R-CHOP was determined for pts with GCB DLBCL (3-year PFS, 79% vs. 70%). No new safety signals were identified. Grade ≥3 adverse events (AEs; 74% vs. 65%) and serious AEs (43% vs. 38%) were more common in the G-CHOP than in the R-CHOP arm. Grade ≥3 AEs of particular interest that were numerically more common with G-CHOP than R-CHOP included neutropenia (57% vs. 48%), infusion-related reactions (45% vs. 32%), infections (54% vs. 44%), and thrombocytopenia (8% vs. 3%). AEs resulting in withdrawal from treatment (12% [84/704] G-CHOP; 9% [60/703] R-CHOP) and AEs with fatal outcome (6% [41/704] G-CHOP; 4% [30/703] R-CHOP) were slightly more common with G-CHOP. The most common AEs leading to death were pneumonia (5 G-CHOP; 6 R-CHOP) and sepsis/septic shock (7 G-CHOP; 3 R-CHOP). Conclusions: The primary endpoint of this study was not met: G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. No unexpected safety signals were identified. Further investigation of outcomes in subgroups is planned. Disclosures Vitolo: Gilead: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Trněný:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Belada:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chua:Roche: Consultancy, Research Funding; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Consultancy. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Kim:Celltrion, Inc.: Consultancy, Honoraria. Pinto:Millennium: Research Funding; Takeda: Honoraria; Helssin: Honoraria; Roche: Honoraria; Celgene: Honoraria; Servier: Honoraria; Janssen: Honoraria. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Oestergaard:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Catalani:Roche: Employment. Nielsen:Hoffmann-La Roche: Employment. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria.

Introduction: Our objective was to develop a prognostic model that predicts progression-free survival (PFS) and overall survival (OS) to enable risk-adapted strategies in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). We retrospectively investigated the value of quantitative image texture features (i.e. 'radiomics' evaluating tumor heterogeneity) using FDG PET/CT data sets in a large, prospective Phase III trial, GOYA (NCT01287741). Methods: In the GOYA trial, which compared obinutuzumab versus rituximab both in combination with CHOP chemotherapy, there was no significant treatment effect between the two arms, thus the two arms were combined for this study. Baseline PET/CT images with regions of interests (ROIs) defined by qualified physicians were analyzed for radiomics features. Image texture features (ITF) were computed using the open-source and validated PET Oncology Radiomics Test Suite (PORTS). The clinical risk factors (International Prognostic Index [IPI], Ann Arbor stage, extranodal disease, bulky disease), cell of origin (COO), standard PET-derived metrics (standard uptake value [SUV]-mean, SUV-max, total metabolic tumor volume [TMTV], total lesion glycolysis [TLG]), SUV histogram metrics (variance, skewness, and kurtosis), and ITF were evaluated for prediction of PFS and OS. TMTV was estimated using adaptive thresholding. Prognostic models were generated by means of multivariate Cox regression analysis, modeling PFS, and OS. In the absence of an independent patient cohort for external model validation, an internal validation, based on c-index and Brier score, was carried out using bootstrap resampling methods. Stratification of patients into risk groups was achieved through maximally selected rank statistics. Multivariate analysis was also carried out on a subgroup of patients with available COO information. Results: The median follow-ups for PFS and OS were 46 and 50 months, respectively. Baseline PET scans were available for 1334 patients with detectable lesions, and 1077 baseline scans were evaluable for calculating ITFs. In the univariate analysis, high TMTV, histogram mean, histogram variance, and the ITFs gray-tone spatial dependence matrices (GTSDM) difference entropy and low gray-level zone length matrix (GLSZM) small zone high gray emphasis were risk factors for PFS, while high TMTV, histogram mean, and the ITF GTSDM inverse difference moment were risk factors for OS (Table 1, showing 95% CI, HR, and p-values for both univariate and multivariate analyses). In multivariate analysis, the risk factors included IPI, Ann Arbor stage, high TMTV, histogram mean, and GTSDM inverse difference moment; results were generally consistent in the multivariate subgroup analysis on patients with COO data available (Table 1). Based on the multivariate model, the probabilities for PFS and OS at 2 and 4 years for individual patients were established (Table 2). By combining TMTV (four categorical groups) with ITF, COO, and predictive clinical factors, three prognostic subgroups of treatment failure risk were identified: low (55% of patients), intermediate (34%), and high (11%). Hazard ratios for high and intermediate risk compared with low risk were 2.16 (p&lt;0.001) and 1.17 (p=0.004) for PFS, and 3.82 (p&lt;0.001) and 1.85 (p&lt;0.001) for OS. The corresponding probability of survival at 2-years for high, intermediate and low risk groups were 87%, 82%, and 75% for PFS, and 94%, 90%, and 82% for OS. The 4-year survival probabilities were 83%, 77%, and 68% for PFS, and 91%, 86%, and 75% for OS (Table 2). For PFS, the accuracy of the Cox model was 0.63 with clinical variables only, 0.65 with the addition of TMTV, and 0.69 with the addition of ITFs; for OS, the corresponding values were 0.63, 0.65, and 0.70. Conclusion: A model including PET-derived quantitative ITF, in addition to significant clinical features, was able to predict survival probability for untreated DLBCL patients with good precision. The proposed PET-based prognostic model may help identify patients who could benefit from risk-adapted treatment modifications or novel approaches. Acknowledgments: GOYA was sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial assistance, under the direction of Lale Kostakoglu, was provided by Katie Smith of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Dalmasso:I-See s.r.l.: Employment. Pierce:Precision Sensing LLC: Equity Ownership. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria. Sehn:Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria. Trněný:Takeda: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bolen:Genentech, Inc.: Employment; F. Hoffmann-La Roche: Equity Ownership. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lee:Genentech: Employment; F. Hoffman-La Roche: Equity Ownership. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Kinahan:Co-founded PET/X LLC: Equity Ownership; Philips Medical: Research Funding; GE Healthcare: Research Funding; F. Hoffmann-La Roche: Consultancy. Chauvie:International Agency on Atomic Energy (IAEA): Consultancy; Co-owner of Dixit srl (spin-off University of Torino): Equity Ownership; F. Hoffmann-La Roche: Research Funding; Fondazione Cassa di Risparmio di Cuneo (CRC): Research Funding; Italian Foundation on Lymphoma (FIL): Research Funding; Italian Association for Cancer Research (AIRC): Research Funding; SIRTEX: Speakers Bureau.

Настоящая работа является первым общим описанием на русском языке двух некрополей Кампокиаро (Кампобассо, Италия) – Виченне и Морионе, датируемых последней третью VII в. – началом VIII в. Культурное содержание некрополей показывает прочные связи с населением центральноазиатского происхождения. Важнейшим признаком некрополей являются захоронения с конем, соответствующие евразийскому кочевому погребальному обряду. Автор поддержал выводы европейских исследователей о том, что с большой долей вероятности некрополи оставлены булгарами дукса–гаштальда Алзеко, зафиксированными Павлом Диаконом в VIII в. на территориях Бояно, Сепино и Изернии. Аналогии некрополей Кампокиаро с погребениями Аварского каганата показывают присутствие в аварском обществе булгар со схожим погребальным обрядом. Из тысяч погребений с конем, оставленных аварским населением, булгарам могла принадлежать большая часть. Авары и булгары составляли основу и правящую верхушку каганата. 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In this article, I explore interstitiality – a concept based on Gil Eyal’s notion of ‘spaces between fields’ – as a potential heuristic lens for observing contemporary elites, applying it to high-ranking figures in the Compagnia San Paolo (CSP). CSP is a banking foundation ( Fondazione di origine bancaria or FOB) that was set up in the 1990s arising from the privatization of the Italian banking sector. After outlining the theoretical underpinnings of interstitiality, I bring the construct to bear on my own empirical work. First, I elucidate what FOBs are and why they may represent a valuable interstitial observatory on a significant segment of power elite. Second, I examine CSP as an emblematic instance of an FOB. Third, I illustrate the main characteristics of CSP’s elites, suggesting that these groups reflect the features of interstitiality insofar as: they merge logics and grammars of justification from different fields; and, given their high degree of mobility across fields, they contribute to disseminating discursive and governmental practices of hybridization. My aim, as advocated for by Mike Savage and Karel Williams, is to enrich the sociological debate on elites by introducing a new conceptual tool.

L’articolo si propone di indagare la trasformazione del ruolo dei principali attori filantropico-finanziari italiani - le fondazioni di origine bancaria - nel policy-making nei campi del welfare e della sanità nel contesto emergenziale della pandemia.Per fare questo, l’articolo si apre introducendo le caratteristiche fondamentali delle FOB e del loro rapporto con le politiche pubbliche per come era fino allo scoppio della pandemia.In particolare ne metteremo in risalto i quattro elementi portanti: 1) la capacità di intervenire in modo tempestivo; 2) la capacità innovativa; 3) la cvolontà di partecipare al policy making su un piano paritario con i decisori pubblici; 4) l’idea di essere migliori sul piano della capacità ideativa, dell’efficacia e dell’efficienza rispetto agli attori pubbliciSuccessivamente, appoggiandoci a dati e ad analisi dei discorsi, analizzeremo se e in che modo questi tre elementi si siano modificati durante la pandemia e con quale esito rispetto alla loro legittimazione nel policy-making.

Il liberalismo, fin dalle sue origini, si basa sul riconoscimento e sul rispetto di tre diritti fondamentali: vita, proprietà e libertà —uno dei fondatori di questa dottrina politica fu il filosofo inglese John Locke (1632-1704)—. Per il liberalismo classico la libertà e la proprietà sono strettamente correlate; i liberali e, in seguito, i libertari, si sono spinti oltre affermando che la libertà e la proprietà sono la stessa cosa. Anche il diritto alla vita è stato riformulato nei termini di proprietà di sé, cioè ognuno è proprietario del proprio corpo e del proprio intelletto, insomma della propria vita. I tre diritti fondamentali —inalienabili— che stanno alla base di ogni altro diritto sono quindi riconducibili al diritto di proprietà. Nel giustificare questo diritto alcuni autori liberali e libertari —come per esempio Murray N. Rothbard (1926-1995)— si sono appoggiati al giusnaturalismo, cioè a una dottrina filosofico-giuridica che si basa sul riconoscimento dell’esistenza di un diritto naturale e razionale universalmente valido, considerato il fondamento di ogni diritto civile. In questo lavoro cercheremo di giustificare il concetto di proprietà abbandonando la sua fondazione giusnaturalistica, che molti contestano per le sue pretese universalistiche —non tutti, infatti, sono disposti a riconoscere l’universalismo dei diritti naturali e l’aura di «sacralità» e «misticismo» che sembrano emanare— sforzandoci di dare un fondamento razionale al rispetto che gli individui tendono ad avere nei confronti dei diritti di proprietà. Per fare ciò utilizzeremo la branca della teoria della scelta razionale che si occupa delle decisioni interattive o strategiche: la teoria dei giochi. In questo passo mostreremo, quindi, servendoci dei principi della teoria evoluzionistica dei giochi (TEG),1 come il concetto di proprietà privata non sia arbitrario, ma sia nato e si sia evoluto per la sua efficienza nel dirimere contese, sia nel mondo animale che tra gli esseri umani. Non sono solo gli esseri umani, infatti, a riconoscere e rispettare la proprietà altrui; anche la maggior parte degli animali distinguono tra lo stato di proprietario e quello di intruso e si comportano in modo diverso qualora si trovino nel primo o nel secondo. Nel primo paragrafo forniremo una breve introduzione ai concetti fondamentali della teoria evoluzionistica dei giochi; nel secondo definiremo il concetto di proprietà privata. Nel terzo considereremo, sulle tracce di David Friedman e degli autori della scuola «austriaca»,2 la funzione sociale della proprietà privata, per passare poi, nel quarto paragrafo, all’analisi della nascita e dell’evoluzione della proprietà, analisi che verrà condotta sulla base della TEG.

Zammit, Marisa, and Erica Dornbusch. A Friend In Hope: a Story About Hope's Journey with a Brain Tumour. Brain Tumor Foundation of Canada, 2008.Zammit, Marisa, Erica Dornbusch, and Carole Baillargeon. Mon amie Claire: L'histoire de Claire et de sa tumeur cérébrale. Foundation canadienne des tumeurs cérébrales, 2009.Zammit, Marisa, Erica Dornbusch, and Rocco Speranza. La mia amica Speranza : Speranza e il suo tumore cerebrale. Fondazione canadese del tumore cerebrale, 2008.In an interview with Daytime television, available on YouTube, author Marisa Zammit explains how the Brain Tumour Foundation of Canada contacted her as an established freelance copy writer to come up with a positive story of hope for and about children with brain tumours. According to Susan Marshall, executive director of the Foundation, no other storybook existed for elementary school aged children in Canada before 2008, when the book was published. It is the personal connection, having a child diagnosed with a brain tumour at the age of 4,that motivated Sharon to commission the publication of A Friend in Hope. Marisa had worked previously with illustrator Erica Dornbusch, who had published other storybooks (e.g. Finding Kate's shoes , Mrs. Goodstory) in the past. Marisa is now a school teacher librarian at Holy Cross Catholic Secondary School in Strathroy, Ontario and she has read the book to her students.A Friend in Hope has definitely accomplished its main objective of giving children, parents, and friends a positive and hopeful outlook on the brain tumour journey. Amy Mathias, the Online Community Engagement Coordinator of the Foundation, indicated that 15,000 copies of the book had been distributed in time for the organization’s 30th Anniversary in 2012. It is thanks to the Ronald McDonald House Charities that printing and distribution of the book were possible. The book addresses a very real need not only in alleviating young patients’ fears, but also in explaining brain tumours and their medical implications to children’s teachers and classmates. In turn, adults diagnosed with brain tumours may also use the storybook to approach the subject with their children.As for the translated versions of the book, Pia di Bacco helped translate from English into French by enlisting the support of youth and staff at her school in Montreal. Similarly, her godson Rocco Speranza commissioned grades 4, 5, and 6 youth and staff at the École East Hill School’s Italian program to translate the storybook from English and French into Italian. The motivation in both translation cases was a result of a family member or a student being diagnosed with a brain tumour and the belief in educating youth about brain tumours. Schools across the English Montreal School Board and beyond in Italy, Australia, Argentina, and the USA have also benefited from the storybook.The story is written from the perspective of a young brain tumour patient’s best friend, Danny, Daniel, or Daniele in English, French, and Italian respectively. Danny is trying to understand and, most of all, support his “best buddy,” Hope, who begins her brain tumour journey. As the author Marisa Zammit expressed in the Daytime interview, Hope, or in Italian Speranza, received that name because “it is hope [speranza] that buoys the character through the hardships of the story.” In French, the character’s name is Claire, whose Latin origin “clarus” means “clear, bright, celebrated” and by extension the word “clear”. The French name too, therefore, is representative of her personality and journey.Part of the story involves references to some of the medical treatments that Hope undergoes: MRI, pharmaceutical drugs, radiation therapy, a special helmet and mouthguard, a hospital’s child life centre, and the effects of various treatments on Hope. In every instance, the story uses the narrator’s voice and point of view to express Hope’s various experiences, Danny’s reactions to them, and his own fears. It is a child’s imagination which makes this topic bearable and allows the illustrations to become particularly powerful, when, for example, Danny sees Hope take some medication, which she says will help her “feel well enough to play with [him].” The illustration, in this case, represents a mountain scape and the children’s game of climbing pillows and cushions as if they were mountain climbers, because as Hope says the medication she takes is the “same medicine mountain climbers use,” (ie. dexamethasone). Another exceptional illustration is the one representing an oceanic world with an octopus and fish, which is how Hope faces the MRI machine and transforms it into a submarine. The illustrations are identical across the translations and the English source text, except for one image representing a hockey player in what appears to be Toronto Maple Leafs colours; however, in the French and Italian translations, which originated in Montreal, the team colours were changed to those of the Montreal Canadiens. Habs fans will no doubt appreciate the sensitivity of the illustrator.All in all the story is very well written and the language is suitable for children from grades 2 to 4; however the concepts that are addressed also make this book relevant to higher grade levels. That said, some grammatical inaccuracies exist within the French translation. Public and school libraries would benefit from access to this book, as would hospital library patrons and those who use Faculty of Education libraries. The health education elements of the story are presented in a very appropriate yet realistic manner for the target audience, who will appreciate having access to such a unique resource.Highly Recommended: 4 out of 4 stars Reviewer: Denis LacroixDenis Lacroix has worked at the University of Alberta Libraries since 2003. He is the romance languages and classics librarian and enjoys reading in French, Spanish, and Italian.

In the Futurist imagination, speed is the essence itself of the existence of modernity: both as the indispensable mechanism in the relationship with contemporary life and as the guiding factor in relationships of the psyche and thought with reality, shaping new individual and collective relations, which were by then projected into the future. -- La Fondazione Antonio Mazzotta Speed, Modernity, and Post-Modernity The concept of speed is prevalent in, and has many implications for, contemporary western society. Speed is simultaneously a form of behaviour required of individuals in their professional lives as the electronic workplace becomes faster and faster, and an experience that many people crave as a form of release from the slow pace of personal or recreational life as this is defined by our physical limitations. In his recent book Faster: The Acceleration of Just About Everything, popular science writer James Gleick discusses instances of where speed functions as a social mechanism that pushes people to function with the speed and efficiency of machines. He describes how speed has become embedded physically, mechanically, and psychologically into almost every aspect of social behaviour, often overwhelming our mental and physical ability to cope with its effects. Speed has become a necessity, a desperation, and a desire to fulfil. The concept of speed is explicitly identified with Modernism, yet it continues to be a focal concept in what may be termed the Postmodern present. Does this mean that speed has surpassed Modernity, that it has sped ahead of its own origins, or does it indicate that Postmodernity is merely the speeding-up of Modernity? This paper does not attempt, in dry academic fashion, to proclaim universal knowledge and provide all the answers to all the questions that could be raised in relation to this topic. The author invites readers to consider the various representations of speed introduced here as the product of a collective western obsession with progress, novelty, and rapid sensationalism. Speed in Futurist Philosophy The Futurist movement has been discussed widely elsewhere, so I will not offer a repetitive description here. It is sufficient for the scope of this paper to refer to the fundamentals of Futurist philosophy as it is defined by F.T. Marinetti in 'The Founding and Manifesto of Futurism', Le Figaro (Paris), 20 February 1909: We affirm that the world's magnificence has been enriched by a new beauty: the beauty of speed. A racing car whose hood is adorned with great pipes, like serpents of explosive breath -- a roaring car that seems to ride on grapeshot is more beautiful than the Victory of Samothrace. We want to hymn the man at the wheel, who hurls the lance of his spirit across the Earth, along the circle of its orbit. Without condoning or embracing the fascist, anti-intellectual, multi-anti-ism elements of Futurist philosophy; I draw attention to this evocative pronouncement of its obsession with speed in order to provide a thematic basis for the material that follows. Speed is defined as a form of great mechanical accomplishment and as an immense intellectual, emotional, and spiritual force that is symbolic of the ideal or progress and human achievement. Speed and Contemporaneity Milan Kundera in his novel Slowness employs the concept of speed to characterise a frenetic ecstasy of the present, which he disparagingly views as archetypally modern: ... the man hunched over his motorcycle can focus only on the present instant of his flight; he is caught in a fragment of time cut off from both the past and the future; he is wrenched from the continuity of time; he is outside time; in other words he is in a state of ecstasy. In that state he is unaware of his age, his wife, his children, his worries, and so he has no fear, because the source of fear is in the future, and a person freed of the future has nothing to fear. (3-4) The 'progress' of the technical revolution, so worshipped by the Futurist thinkers, is for Kundera an experience that is more mental and psychological than it is physical, due to the inability of the human body to produce the thrill of speed to the extent that machines can. He contrasts mechanically-induced speed to that produced by our own bodies: As opposed to a motorcyclist, the runner is always present in his body, forever required to think of his blisters, his exhaustion; when he runs he feels his weight, his age, more conscious than ever of himself and of his time of life. This all changes when man delegates the faculty of speed to a machine: from then on, his own body is outside the process, and he gives over to a speed that is non-corporeal, non-material, pure speed, speed itself, ecstasy speed. (4) For Kundera, "Speed is the form of ecstasy the technical revolution as bestowed on man." This statement accords with the Modernist vision of speed as the motif of industrial and social progress, but it does not really elucidate what characteristics the speed itself possesses. The Characteristics of Technologically Enabled Speed Interpreting from Kundera's thoughts on speed, it is possible to surmise that: The speed produced must be significantly beyond that capable of being produced by the unaided human body; The technical production of speed and the reliance on sophisticated equipment to do this paradoxically produces a purely non-corporeal, metaphysical or psychological experience that is outside time and beyond immediate physical consequences; and Speed is a form of ecstatic experience that is comparable to other forms of ecstasy, such as sexual or religious experience, or the use of psychotropic drugs. In contemporary society the experience of speed is determined by these three concepts. The Personal I know of no better way to experience speed in a raw, immediate, and sensory-fulfilling way than to ride a motorcycle faster than is legally permitted. Unlike other forms of mechanical travel -- cars, aircraft, trains -- motorbikes offer a direct way to really feel speed. The image of the motorcyclist in Slowness is evocative for me because Kundera's language (even in translation) gives my immediate experience a lyrical context. In other forms of transport, the traveller is too far removed from many of the sensations of speed, even when travelling at greater speeds than a bike can manage. Cars are safe, and you can speed in them more safely than on a bike. The relative distance from the road and the wind is greater, however, and the traveller is thus further removed from the elements that make the sensation of speed so intoxicating. When riding a motorcycle, the wind hits you roughly at higher speeds, gently at lower speeds, and moves around you unpredictably, pushing the bike in different directions. In other forms of transport, the traveller is too far removed from many of the sensations of speed, even when travelling at greater speeds than a bike can manage. Cars are safe, and you can speed in them more safely than on a bike. The relative distance from the road and the wind is greater, however, and the traveller is thus further removed from the elements that make the sensation of speed so intoxicating. When riding a motorcycle, the wind hits you roughly at higher speeds, gently at lower speeds, and moves around you unpredictably, pushing the bike in different directions. In other forms of transport, the traveller is too far removed from many of the sensations of speed, even when travelling at greater speeds than a bike can manage. Cars are safe, and you can speed in them more safely than on a bike. The relative distance from the road and the wind is greater, however, and the traveller is thus further removed from the elements that make the sensation of speed so intoxicating. When riding a motorcycle, the wind hits you roughly at higher speeds, gently at lower speeds, and moves around you unpredictably, pushing the bike in different directions. Racing The rebellious, renegade idea of driving or riding illegally fast on public roads is examined and discussed at the Flat Out Website (not that this article condones breaking the law). A far safer and less costly alternative is watching motor-racing on television (or better still actually at the track). In Formula 1, the ultimate form of international motor-racing, speed is sought and worshipped in many forms, from the speed of the cars and the drivers themselves to the speed of the associated technologies used by the teams. What fascinates most spectators, however, is the desire of the drivers to take risks in order to go faster than anyone else, and go faster than they have ever gone before. Legendary drivers like Stirling Moss, Gilles Villeneuve, Nigel Mansell, Ayrton Senna, and Michael Schumacher have earnt respect and admiration in relation to the intensity of the experience of speed that they are able to share with their fans. The number of races they win is immaterial in relation to the style with which they drive. Villeneuve, for example, only won 6 races, yet he is worshipped more than drivers who have won many more than that because his style of driving demonstrated the purity of speed. He desired the thrill of speed more than the glory of victory. Vicariously, spectators of speed share in the glory and sensationalism it creates. Speed is meant to be fun for both the participant and the spectator; it does not have to mean anything more than this. Visualise a Bullet Train or TGV slicing through glorious Japanese or French countryside. Marvel at a 500cc GP rider like Mick Doohan sliding his bike through a smooth fast corner to the adulation of thousands. There is only one appropriate response. As Lt. Pete 'Maverick' Mitchell, Tom Cruise's character in the hit 1980s film Top Gun, says, "I feel the need, the need for speed!" References Gleick, James. Faster: The Acceleration of Just About Everything. London: Little, Brown, and Company, 1999. Kundera, Milan. Slowness. London: Faber, 1996. Marinetti, F.T. "The Founding and Manifesto of Futurism". Le Figaro (Paris) 20 Feb. 1909. 1 Feb 2000 <http://www.futurism.fsnet.co.uk/manifestos/manifesto01.htm>. Citation reference for this article MLA style: Brian Ward. "Speed." M/C: A Journal of Media and Culture 3.3 (2000). [your date of access] <http://www.api-network.com/mc/0006/speed.php>. Chicago style: Brian Ward, "Speed," M/C: A Journal of Media and Culture 3, no. 3 (2000), <http://www.api-network.com/mc/0006/speed.php> ([your date of access]). APA style: Brian Ward. (2000) Speed. M/C: A Journal of Media and Culture 3(3). <http://www.api-network.com/mc/0006/speed.php> ([your date of access]).